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ARTICLE IN BRIEF

A new study of mice and humans reported that tiny tunnels run from skull bone marrow to the lining of the brain and may provide a direct route for immune cells responding to injuries caused by stroke and other brain disorders.

Scientists at Massachusetts General Hospital have discovered microscopic tunnels in the skull that transport inflammatory neutrophils from the bone marrow to the membranes covering the brain. This is the first evidence that these channels exist, and the scientists found them in both mice and humans.

While the discovery provides only early clues about the role of these channels, it suggests that they could play a role in triggering too much inflammation in brain diseases, and further that the channels could potentially be used for blocking inflammatory cells or providing a mechanism for delivering medicines into the brain. The study was published in September in Nature Neuroscience.

“Our discovery shows that skull bone marrow has a direct connection to the meninges through these microscopic channels,” said Matthias Nahrendorf, MD, PhD, professor of radiology at Massachusetts General Hospital and Harvard Medical School. His lab studies the role of immunity in cardiovascular disease. “We now need to figure out whether these channels in the skull have an impact on inflammatory processes in brain diseases,” Dr. Nahrendorf said.

STUDY METHODS, FINDINGS

It has long been known that bone marrow is made in large bones of the body — the arms, legs, pelvis, and the skull. It has long been thought that an injured body triggered the production of inflammatory cells in the bone marrow but proximity to the injury didn't matter.

Fanny Herisson, MD, a research fellow in radiology, devised a method to test whether proximity does play a role. Dr. Herisson and her colleagues injected a fine needle into the tibia in the leg or skull and induced a stroke in mice. Fluorescent dyes labeled the cells in the marrow from both sites, and they used flow cytometry to measure what was happening.

They used magnetic resonance imaging to examine the inner layer of the skull, the space that separates the marrow from the meninges. That is when they discovered these microscopic vascular channels that were taking the neutrophils and monocytes and shuttling them to the surface of the brain – against the normal flow of blood into the marrow. Following stroke, there was a significant drop in neutrophils and monocytes in the skull marrow compared to marrow from the leg. They induced encephalitis in mice and found the same response.

By contrast, there was not a preference on where the marrow was coming from — the leg or the skull — during a myocardial infarction.

They identified similar channels in skull marrow in three patients undergoing brain surgery. They used a high-resolution computed tomography of a piece of skull removed during a craniectomy to observe these channels.

Dr. Nahrendorf said that he believes that these channels are “conduits for an inflammatory cross-talk between the marrow and the central nervous system and that it is quite different from any other vasculature.”

The researchers are now trying to determine the relevance of these channels and whether inflammatory substances produced during a brain disease, infection or injury could send signals to the skull marrow to get inflammatory cells to respond quickly. They will also test chronic injury, which may trigger a different response by the skull marrow.

“Since many brain disorders have inflammatory components, it would be great to learn how the channels contribute to those diseases and whether modulating their contributions could change outcomes,” he said. They will try to block cells in the channels to see whether it decreases inflammation and changes the outcome of the pathology.

“Another idea is that the channels could serve as a route of drug delivery, allowing transport to the meninges of drugs delivered into the skull marrow,” he added.

EXPERT COMMENTARY

“I think this is a very interesting work,” said Jonathan Kipnis, PhD, in the department neuroscience in the Center for Brain Immunology and Glia at the University of Virginia. “If meningeal immunity is solely or primarily being fed uniquely through skull bone marrow, it must mean something. I am not sure we know the importance of these channels and if soluble molecules, such as antibodies for example, could also go through them. This is another piece of the brain immunity puzzle, and it makes the picture only more complex and more exciting.”

“This is a milestone that puts forth a new hypothesis about how the brain and the immune system interact,” added Katerina Akassoglou, PhD, senior investigator at the Gladstone Institute of Neurological Disease, and professor of neurology at the University of California, San Francisco. “This vascular structure, this pathway, had been missed. We need to understand how these channels — this ‘short-cut’ that the study described — affect disease.”

Dr. Akassoglou said that the finding will generate a lot of important research. “Do other inflammatory cells use this route and does the mechanism have a hand in chronic inflammation? It is possible that the pathway functions differently throughout the degenerative process,” she added. “Also, is it a one-way mechanism that cells can get into the brain or can cells get out too? What role does it have with the blood brain barrier? How does normal aging affect the channels?”

“This finding will provide clues to mechanisms that involve post-inflammatory processes in stroke,” added Costantino Iadecola, MD, the Anne Parrish Titzell professor of neurology and director and chair of the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. “In stroke, the meninges get inflamed. Now, we understand a bit more about what is going on and how these cells are infiltrating the brain. It's like having a beeline to the meninges directly through the skull.”

He cited a study by Dorian McGavern, PhD, a senior investigator in the viral immunology and intravital imaging section at the National Institute of Neurological Disorders and Stroke, that showed one can apply small molecular weight compounds to the skull and they can get through into the brain. “There are all kinds of new ways we can test to see how we can get drugs into the brain through skull marrow or see if we can change the inflammatory environment in the marrow itself.”

Francesca Bosetti, PhD, program director for stroke research at the National Institute of Neurological Disorders and Stroke, called the finding “novel,” and said that “it makes perfect sense. You would rather the first responders be close to the scene. That these channels also exist in the human brain is intriguing.”

She said that the team just received a grant through the National Institutes of Health Blueprint for Neuroscience Research to continue investigating skull marrow crosstalk with the central nervous system.

“We don't know in which situations these inflammatory cells are called on,” added Dr. Bosetti. “The findings could be applicable not just to stroke and encephalitis, but also to many other neurological diseases with a neuroinflammatory component, including Alzheimer's disease, traumatic brain injury, and multiple sclerosis.”